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Unusual central nervous system toxicity in a phase I study of N1N11diethylnorspermine in patients with advanced malignancy

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Abstract

The objectives of this study were to determine the dose limiting toxicity (DLT) and other major toxicities, the maximum tolerated dose (MTD) and the human pharmacokinetics of N1N11diethylnorspermine (DENSPM), a new polyamine analog which in experimental systems inhibits the biosynthesis of intracellular polyamines and promotes their degradation by inducing the enzyme spermine/spermidine N-acetyl transferase.

These objectives were incompletely achieved because of the occurrence of an unusual syndrome of acute central nervous system toxicity which forms the basis of the present report. Fifteen patients with advanced solid tumors were entered into a phase I study of DENSPM given by a 1h i.v. infusion every 12h for 5 days (10 doses). The starting dose was 25 mg/m2/day (12.5 mg/m2/dose) with escalation by a modified Fibonacci search.

Doses of 25 and 50 mg/m2/day were tolerated with only minor side effects of facial flushing, nausea, headache and dizziness (all grade I). At doses of 83 and 125 mg/m2/day, a symptom complex of headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia, was seen in 3 patients, one after 2 courses of 83 and 2 after 1 course of 125 mg/m2/day. This syndrome occurred after drug administration was complete and the patients had returned home. Lesser CNS toxicity was seen in 2 other patients at lower daily doses. Preliminary pharmacokinetics of DESPM measured in plasma by HPLC in 8 patients showed linearity with dose and a rapid plasma decay with a t2 of 0.12h.

We conclude that great caution is warranted in administering DENSPM on this schedule at doses of ≥ 83 mg/m2/day.

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Authors and Affiliations

  1. Departments of Investigational Therapeutics and Solid Tumor Oncology, Roswell Park Cancer Institute (RPCI), Buffalo, New York, USA

    Patrick J. Creaven, Raymond Perez, Lakshmi Pendyala, Neal J. Meropol, Gregory Loewen, Ellis Levine, Elmer Berghorn & Derek Raghavan

Authors
  1. Patrick J. Creaven
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  2. Raymond Perez
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  3. Lakshmi Pendyala
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  4. Neal J. Meropol
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  5. Gregory Loewen
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  6. Ellis Levine
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  7. Elmer Berghorn
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  8. Derek Raghavan
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Creaven, P.J., Perez, R., Pendyala, L. et al. Unusual central nervous system toxicity in a phase I study of N1N11diethylnorspermine in patients with advanced malignancy. Invest New Drugs 15, 227–234 (1997). https://doi.org/10.1023/A:1005827231849

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